Neuronal Firing in Human Epileptic Cortex: The Ins and Outs of Synchrony During Seizures

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1 Current Literature In Basic Science Neuronal Firing in Human Epileptic Cortex: The Ins and Outs of Synchrony During Seizures Evidence of an inhibitory restraint of seizure activity in humans. Schevon CA, Weiss SA, McKhann Jr G, Goodman RR, Yuste R, Emerson RG, Trevelyan AJ. Nat Commun 2012;3:1060. doi: /ncomms2056 The location and trajectory of seizure activity is of great importance, yet our ability to map such activity remains primitive. Recently, development of multi-electrode arrays for use in humans has provided new levels of temporal and spatial resolution for recording seizures. Here, we show that there is a sharp delineation between areas, showing intense hypersynchronous firing indicative of recruitment to the seizure, and adjacent territories where there is only low-level, unstructured firing. Thus, there is a core territory of recruited neurons and a surrounding ictal penumbra. The defining feature of the ictal penumbra is the contrast between the large amplitude EEG signals and the low-level firing there. Our human recordings bear striking similarities with animal studies of an inhibitory restraint, indicating they can be readily understood in terms of this mechanism. These findings have important implications for how we localize seizure activity and map its spread. Single-Neuron Dynamics in Human Focal Epilepsy. Truccolo W, Donoghue JA, Hochberg LR, Eskandar EN, Madsen JR, Anderson WS, Brown EN, Halgren E, Cash SS. Nat Neurosci 2011;14: Epileptic seizures are traditionally characterized as the ultimate expression of monolithic, hypersynchronous neuronal activity arising from unbalanced runaway excitation. Here, we report the first examination of spike-train patterns in large ensembles of single neurons during seizures in persons with epilepsy. Contrary to the traditional view, neuronal spiking activity during seizure initiation and spread was highly heterogeneous, not hypersynchronous, suggesting complex interactions among different neuronal groups, even at the spatial scale of small cortical patches. In contrast to earlier stages, seizure termination is a nearly homogenous phenomenon followed by an almost complete cessation of spiking across recorded neuronal ensembles. Notably, even neurons outside the region of seizure onset showed significant changes in activity minutes before the seizure. These findings suggest a revision of current thinking about seizure mechanisms and point to the possibility of seizure prevention based on spiking activity in neocortical neurons. Commentary Epileptic seizures propagate extensively across the brain. The associated electrophysiological mass phenomena can be captured by scalp or intracranial electroencephalography. Recent evidence shows the initiating mechanisms of seizures operate at the smaller scale of neuronal ensembles, producing phenomena such as high-frequency oscillations (1, 2) and microseizures (3, 4) that are best detected at a tighter spatial resolution of local field potentials recorded by microelectrodes. More recently, researchers have started using microelectrodes to analyze the activity of large numbers of individual neurons during seizures in neocortex (5) and hippocampus (6) and to relate this activity Epilepsy Currents, Vol. 13, No. 2 (March/April) 2013 pp American Epilepsy Society to the corresponding macroscopic EEG recordings. The main focus of this commentary is the most recent of these studies by Schevon et al., which provides potential solutions to puzzles arising from previous neocortical work. The idea that seizures represent hypersynchrony goes back at least to the 1950s (7). However, until recently, recordings from people with epilepsy suggested that neuronal firing is not hypersynchronous, despite the presence of large rhythmic arguably hypersynchronous field potentials. Early studies with single microelectrodes (8, 9) found no evidence for extensive or synchronous neuronal firing during seizures. The advent of dense multi-electrode arrays allows sampling of the activity of many neurons within local regions in the brain. Schevon et al. and Trucculo et al. both used microelectrode (Utah) arrays in the neocortex of epileptic patients. The arrays sampled 96 sites at a depth of 1 mm within a 4 mm 4 mm area. Closely spaced penetrating electrodes are likely to 100

2 Dissociation of synchronization of neurons and field potentials FIGURE 1. Microwire recording of a medial temporal lobe seizure acquired at the Dept. of Epileptology, University of Bonn. Local field potentials and unit activity from a bundle of eight microwires in the hippocampus are displayed in corresponding colors. cause more damage to the tissue than the depth microelectrodes used by Bower et al. (6) in the medial temporal lobe. This means the arrays must be targeted to areas likely to be resected. Fortunately, this is exactly where they need to be to study the initiation of seizures. All three studies found recordings consistent with earlier evidence of heterogeneous changes in neuronal firing during electrographic seizure activity, both increases and decreases in firing rate with many units not changing (one-third in Trucculo et al. and two-thirds in (6)). In Schevon et al., this activity was found to be unrelated to the field potentials recorded in the same areas; this is surprising because the simplest model would have local neurons driving the synaptic currents that generate most of the field potentials or responding to those synaptic currents. Results of Schevon et al. differ from those of Truccolo et al. in finding a second class of activity: propagating areas of hypersynchronous neuronal firing at rates > 30 baseline. This class of activity can also be found in microwire seizure recordings from human medial temporal lobe (Figure 1). Interpretation of the relationship between these two fundamentally different states is based on evidence presented on epileptiform activity in normal mouse cortex in vitro when exposed to a convulsant medium (with lowered magnesium ion concentration). A combination of live-cell imaging and patch clamp recording revealed the epileptiform activity depended on rapid and synchronous firing of clusters of neurons that propagated slowly across the cortical slice. Crucially, areas ahead of the advancing region of neuronal firing experienced a barrage of excitatory and inhibitory synaptic activity, with inhibition dominating and restraining propagation. When the epileptic front had passed, neurons fired briskly and synchronously with phase delays revealing coupling much faster than the epileptic propagation velocity. Human recordings by Schevon et al. revealed patterns of firing and relationships with local field potentials very similar to those in the mouse model. They failed to place their arrays over the sites of seizure initiation (although the good outcomes for surgery suggest they were not far off). The advancing wave of hypersynchronous neuronal hyperactivity was preceded by large rhythmic field potentials that were not synchronized with neuronal firing. The human recordings also resembled the mouse model in three ways: a sharp boundary between these two classes of activity, slow propagation velocity of hyperactiv- 101

3 Dissociation of synchronization of neurons and field potentials ity, and much faster synchronization during the period of rapid firing. The experimental and clinical parts of this study provide a good example of how well the two approaches can complement each other. Further, the clinical evidence of hypersynchronous neuronal hyperactivity is also encouraging for animal models of epilepsy where it usually features prominently. Unit recordings can provide new insights into the process of transition to seizure and seizure prediction. Truccolo et al. observed significant changes in firing rates during the 3-min interval before a seizure from those during the previous 30 min. Based on the number of neurons exhibiting these changes - averaged across different seizures from a given patient and thus corresponding to an algorithmic sensitivity in the range of 50% - they assessed the specificity by sampling random 3-min segments from interictal control epochs away from the seizure. Specificity values for these control epochs ranged between 44% and 94%, thus failing to reach statistical significance for any of the control epochs (p > 0.06). Nevertheless, as the authors correctly state in their cautious interpretation of these findings, these are promising preliminary results that warrant further research. Another interesting aspect of the work of Trucculo et al. is that seizure termination was accompanied by a prominent decrease in neuronal firing activity, observed both for putative principal cells and interneurons (classified electrographically). In light of results by Schevon et al., this shutdown of activity could possibly be caused by feedforward inhibition generated by a homogeneous activation of inhibitory neurons at a different location. The varying degrees of stereotypical firing patterns between seizures in the same patient (6) might likewise depend on whether or not neurons are actually being recruited by the propagating wave of seizure spread (Figure 1). One implication from these studies is that the core of the seizure-generating zone is spatially tight, elusive for 4 mm square arrays of microelectrodes. This is interesting scientifically but also has practical implications: The location of the first signs of electrographic seizure activity will be related to the epileptogenic zone, but the length of synaptic projections from the neurons in this zone means that the spatial resolution of field potential recordings is compromised. Perhaps the most striking aspect of these findings is the clear dissociation between the high-amplitude rhythmic field potentials in the lower part of the frequency spectrum (2 50 Hz) thought to reflect synaptic input activity, and the multiunit firing activity reflecting the output of these neurons. While these rhythmic field potentials are traditionally considered the hallmark of propagating seizure activity, they appear to reflect the spatially extended synaptic inputs elicited from a much more focal region of synchronously firing neurons located elsewhere. Actual recruitment of neurons in areas exhibiting electrographic signs of seizure activity may or may not occur; currently, this can be determined only by monitoring the neurons output firing (Figure1; Figure 4 in Schevon et al.). by Florian Mormann and John G. R. Jefferys References 1. Bragin A, Engel JJ, Wilson CL, Fried I, Mathern GW. Hippocampal and entorhinal cortex high-frequency oscillations ( Hz) in human epileptic brain and in kainic acid-treated rats with chronic seizures. Epilepsia 1999;40: Jirsch JD, Urrestarazu E, Levan P, Olivier A, Dubeau F, Gotman J. High-frequency oscillations during human focal seizures. Brain 2006;129: Schevon CA, Ng SK, Cappell J et al. Microphysiology of epileptiform activity in human neocortex. J Clin Neurophysiol 2008;25: Stead M, Bower M, Brinkmann BH, Lee K, Marsh WR, Meyer FB, Litt B, Van Gompel J, Worrell GA. Microseizures and the spatiotemporal scales of human partial epilepsy. Brain 2010;133: Jobst BC. What is a seizure? Insights from human single-neuron recordings. Epilepsy Currents 2012;12: Bower MR, Stead M, Meyer FB, Marsh WR, Worrell GA. Spatiotemporal neuronal correlates of seizure generation in focal epilepsy. Epilepsia 2012;53: Penfield W, Jasper H. Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown, Babb TL, Wilson CL, Isokawa-Akesson M. Firing patterns of human limbic neurons during stereoencephalography (SEEG) and clinical temporal lobe seizures. Electroencephalogr Clin Neurophysiol 1987;66: Wyler AR, Ojemann GA, Ward AA, Jr. Neurons in human epileptic cortex: Correlation between unit and EEG activity. Ann Neurol 1982;11:

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5 American Epilepsy Society Epilepsy Currents Journal Disclosure of Potential Conflicts of Interest Section #1 Identifying Information 1. Today s Date: Jan 2, First Name Florian Last Name Mormann Degree MD, PhD 3. Are you the Main Assigned Author? Yes No If no, enter your name as co-author: Florian Mormann 4. Manuscript/Article Title: Neuronal Firing in Human Epileptic Cortex: The Ins and Outs of Synchrony During Seizures 5. Journal Issue you are submitting for: Section #2 The Work Under Consideration for Publication Did you or your institution at any time receive payment or services from a third party for any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation, statistical analysis, etc.)? Complete each row by checking No or providing the requested information. If you have more than one relationship just add rows to this table. Type No Money Paid to You Money to Your Institution* Name of Entity Comments** 1. Grant $481, Consulting fee or honorarium 3. Support for travel to meetings for the study or other purposes 4. Fees for participating in review activities such as data monitoring boards, statistical analysis, end point committees, and the like 5. Payment for writing or reviewing the manuscript 6. Provision of writing assistance, medicines, equipment, or administrative support. 7. Other * This means money that your institution received for your efforts on this study. ** Use this section to provide any needed explanation. DFG Sachmittelbeihilfe MO 930/4-1 German Research Council Page 2 5/15/2013

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8 American Epilepsy Society Epilepsy Currents Journal Disclosure of Potential Conflicts of Interest Section #1 Identifying Information 1. Today s Date: 3 Jan First Name John Last Name Jefferys Degree PhD 3. Are you the Main Assigned Author? Yes No If no, enter your name as co-author: 4. Manuscript/Article Title: Neuronal Firing in Human Epileptic Cortex: The Ins and Outs of Synchrony During Seizures 5. Journal Issue you are submitting for: February 2013 Section #2 The Work Under Consideration for Publication Did you or your institution at any time receive payment or services from a third party for any aspect of the submitted work (including but not limited to grants, data monitoring board, study design, manuscript preparation, statistical analysis, etc.)? Complete each row by checking No or providing the requested information. If you have more than one relationship just add rows to this table. Type No Money Paid to You Money to Your Institution* Name of Entity Comments** 1. Grant 2. Consulting fee or honorarium 3. Support for travel to meetings for the study or other purposes 4. Fees for participating in review activities such as data monitoring boards, statistical analysis, end point committees, and the like 5. Payment for writing or reviewing the manuscript 6. Provision of writing assistance, medicines, equipment, or administrative support. 7. Other * This means money that your institution received for your efforts on this study. ** Use this section to provide any needed explanation. Page 2 5/15/2013

9 Section #3 Relevant financial activities outside the submitted work. Place a check in the appropriate boxes in the table to indicate whether you have financial relationships (regardless of amount of compensation) with entities as described in the instructions. Use one line for each entity; add as many lines as you need by clicking the Add box. You should report relationships that were present during the 36 months prior to submission. Complete each row by checking No or providing the requested information. If you have more than one relationship just add rows to this table. Type of relationship (in alphabetical order) No Name of Entity Comments** 1. Board membership Money Paid to You Money to Your Institution* 2. Consultancy Yes Kansas City Medical Research Institute 3. Employment 4. Expert testimony 5. Grants/grants pending 6. Payment for lectures including service on speakers bureaus Yes GSK lecture to epilepsy specialist nurses 7. Payment for manuscript preparation. 8. Patents (planned, pending or issued) 9. Royalties 10. Payment for development of educational presentations 11. Stock/stock options 12. Travel/accommodations/meeti ng expenses unrelated to activities listed.** 13. Other (err on the side of full disclosure) * This means money that your institution received for your efforts. ** For example, if you report a consultancy above there is no need to report travel related to that consultancy on this line. Section #4 Other relationships Are there other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing, what you wrote in the submitted work? No other relationships/conditions/circumstances that present a potential conflict of interest. Yes, the following relationships/conditions/circumstances are present: Thank you for your assistance. Page 3 5/15/2013

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